Anaplastic lymphoma kinase (ALK) inhibitors are efficient anti-cancer drugs acting on tumours with affecting anaplastic lymphoma kinase (ALK) such as an EML4-ALK translocation. Ceritinib (trade name Zykadia), an ALK inhibitor in the form of 150 mg of oral capsule, is a drug for the treatment of lung cancer sold by Novartis Pharmaceuticals Corp. It was approved in April 2014 by the Food and Drug Administration. It is indicated for the treatment of patients with ALK-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. Ceritinib is described chemically as 5-Chloro-N4-[2-[(1methylethyl)sulfonyl]phenyl]-N2-[5-methyl-2-(1-methylethoxy)-4-(4-piperidinyl)phenyl]-2,4-pyrimidinediamine. The molecular formula for ceritinib is C28H36N5O3ClS; the molecular weight is 558.14 g/mole, and has the structural formula shown as Formula I:

International patent application Publication No. WO2008/073687 and Journal of Medicinal Chemistry, 2013, 56(14):5675-5690 (a review) disclose the preparation method of ceritinib and closely related analogues. The method is based on 2-(isopropylsulfonyl)benzenamine (8a) and 2,4,5-trichloropyrimidine as starting materials; it first reacts with 4-bit nucleophilic substitution to get an intermediate 2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (9a), then the compound and the other intermediate tert-butyl 4-(4-amino-5-isopropoxy-2-methylphenyl)piperidine-1-carboxylate (13b)(it's given from 2-chloro-4-fluoro-1-methylbenzene, as shown below occurs the coupling reaction. Finally, the resultant removes N-protecting group to get ceritinib (Formula I), the synthetic route of ceritinib is shown below.

Most of the procedures of the reactions of the above solutions need isolation and purification by column chromatography, which is a tedious operation with low efficiency and is not suitable for industrial amplification. More importantly, in the reduction reaction, compound 12b (4-(5-isopropoxy-2-methyl-4-nitrophenyl)pyridine) is reduced in presence of platinum oxide (PtO2) catalyst to the compound 13b, and the key coupling step uses Pd(OAc)2 as a catalyst. The use of heavy metal in these two reactions results in a greater amount of solid waste, having a great influence on the final product of metal residues.